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ABSTRACT
Background. The interaction between acenocoumarol and omeprazole is described to be possible in different forums even though the evidence shows that both can be prescribed together safely.
Aim. To evaluate the the introduction of omeprazole on the effect of acenocoumarol in primary care clinical practice.
Design and setting. Cross-sectional study with prospective follow-up of the patients treated with acenocoumarol for 18 months period in 5 health urban areas. 
Method. Association of age, sex, anticoagulant dose, indication and INR values according the use of acenocoumarol and PPI.
Results. Of the 260 patients with acenocoumarol (with 3,280 INR measurements) at the start, 126 (48.5%) had previously been with some PPI (97 took omeprazole, mean INR of 2.43), 134 patients were not taking any PPI at the start of the study. Of the patients not previously treated with a PPI, 52 started with some PPI during the monitoring period; in 47 cases the PPI was omeprazole, 33 (70.2%) of which had an INR within the therapeutic range just before the administration of omeprazole. After the administration of omeprazole, 30 patients (90.9%) remained within the therapeutic range. The mean INR values just before and after the administration of omeprazole were 2.47 and 2.46 respectively (P = 0.814). 
Conclusion. The addition of omeprazole to patients treated with acenocoumarol did not modify the INR values, reaffirming that there is no drug interaction. Long-term concomitant treatment with acenocoumarol and omeprazole is compatible with the INR measures within the target range.
Keywords. Acenocoumarol, omeprazole, drug interactions. 
INTRODUCTION
During the 90s, coumarins demonstrated their efficacy in the prevention of ischemic stroke in patients with atrial fibrillation. From then on, clinical practice guidelines have included these anticoagulants. Due to its widespread use in Anglo-Saxon countries, warfarin is the most studied anticoagulant1. Acenocumarol is currently widespread in the Spanish population and primary care plays an important role in its control.2,3 Coumarin therapy does not require gastric protection, but the concomitant use of drugs that may increase the risk of gastrointestinal bleeding, the advanced age of anticoagulated patients, and their multiple pathologies make it common for PPIs to be prescribed.4 Their high level of efficiency and low toxicity make PPIs one of the most overprescribed drugs in the world. It is estimated that between 25% and 70% of the PPI prescriptions do not have the appropriate indication.5-8

Their co-administration in polymedicated patients and the narrow therapeutic margin of oral anticoagulants make lists of drug interactions absolutely essential9-10. Despite the available evidence indicating that its association with omeprazole does not affect coagulation in rats11 and its lack of clinical significance in healthy volunteers12-16, the lists not only maintain this interaction but also extrapolate this to acenocoumarol.
Although a retrospective study of 118 patients17 and another short-term prospective study of 8 patients18 showed no interactions between acenocoumarol and omeprazole, this interaction is described to be possible in case-based and in retrospective studies19-21 and is used as a commercial strategy by some pharmaceutical companies to promote newer and more expensive PPIs,22 drugs for which there is less experience of using in patients receiving coumarin anticoagulant. For this reason, a long-term study was performed to evaluate the INR values in patients undergoing treatment with acenocoumarol and omeprazole, with the INR controls carried out in primary healthcare centres. 


METHODS
We designed a cross-sectional study with prospective longitudinal follow-up of all patients receiving coumarin anticoagulant at the beginning of an 18-month period (January 1st 2014 to June 30th 2015) with the objective of assessing the interaction between acenocoumarol and PPI by evaluating the INR values in patients treated with acenocoumarol and with or without a PPI (concomitant treatment at the beginning of the study or initiated during the follow-up period). The secondary objective was to record all clinically significant adverse effects arising from the interaction between acenocoumarol and the different PPIs under clinical practice conditions in primary healthcare centres.
Using the Catalan Health Institute computerized clinical history database (eCAP), we identified the entire population that was receiving oral anticoagulant therapy in five primary healthcare centres in the city of Barcelona (Raval Sud, Raval Nord, Bes�s, Sant Mart�, and Poblenou). We included all those patients controlled by their GP and excluded those supervised in Hospital Hematology Services because neither the INR values nor the possible adverse effects were available in their clinical histories. Regardless of the treatment with PPI (concomitant from the beginning of the study, initiated during the monitoring period or not initiated at any time), variations in INR were compared, statistical significances were analysed, and the possible clinically significant adverse effects between acenocoumarol and the different PPIs were recorded. 
From the medical history review, the information extracted was recorded in the data collection sheet with respect to the following variables: age; sex; principal indication of the anticoagulant treatment (1. atrial fibrillation; 2. dilated cardiomyopathy; 3. mitral valve disease or left atrial hypertrophy >55 mm; 4. mechanical heart valve prostheses; 5. biological heart valve prosthesis; 6. pulmonary embolism or deep vein thrombosis; or 7. combinations of these indications); monthly check-up and date of appointment; INR value; observer�s interpretation of the INR (normal, within the therapeutic range of INR of 2�3; supratherapeutic, above the upper limit of the therapeutic range; infratherapeutic, below the lower limit of the therapeutic range); dosage of acenocoumarol from the previous month (mg/week); dosage of acenocoumarol for the present month (mg/week); duration of the treatment with acenocoumarol; PPI treatment: active ingredient (omeprazole, lansoprazole, pantoprazole, rabeprazole, or esomeprazole); date of starting the PPI; dose, changes (suspension, switch to a different PPI); complications or significant adverse effects (with a description). 
Absolute numbers and percentages of the total have been used in the statistical analysis to describe the qualitative variables. The quantitative variables were described using the central tendency (mean and median) and the distribution (standard deviation, maximum and minimum values).
For the bivariate analysis, the Chi-square test was used to test qualitative variables, while quantitative variables were tested using the T-test and, in the cases for which normal conditions were not met, the Mann-Whitney U-test was used. Values of 5% were taken as significant (P d" 0.05) in all cases. 
The study had the ethical approval (ref P12/33) by the Idiap Jordi Gol ethical committee in October 3rd 2013. The authors declare no conflict of interest. 
RESULTS 
From a total of 144.503 patients assigned to the five healthcare centres, 426 patients were treated with an anticoagulant drug. Of those, we excluded the ones supervised in hospitals and selected the 260 patients receiving acenocoumarol who were controlled in primary healthcare centres (61%). The mean age of those 260 patients was 75.0 years (SD 9.8), and 53.8% were women. The most common indication was anticoagulation due to atrial fibrillation (in 88.2% of the cases; see table 1). The mean baseline INR was 2.48 (SD 0.59), and INR values were within the therapeutic range (INR 2�3) in 53.3% of the tests. At the moment of inclusion in the study, patients had received acenocoumarol treatment on an average of 24 months (with a range between 1 and 180 months), and the mean dosage of the previous regimen was 12.48 mg/week of acenocoumarol (range 1�36 mg).
Of the patients treated with acenocoumarol at the start of the study, 126 of 260 (48.5%) were previously treated with some type of PPI (figure 1), of which 97 took omeprazole with a mean INR of 2.43. 21 patients received pantoprazole and 8 patients were treated lansoprazole.
Among the 134 (51.5%) patients not treated with a PPI at the beginning of the study, 52 were prescribed a PPI by their GP or an specialist during the monitoring period. The mean INR values were 2.45 (just before the PPI) and 2.43 (just after; p = 0.586). The percentage of INR results within the therapeutic range of good control (INR between 2�3) was 63.8% (just before) and 59.6% shortly after the PPI introduction (P = 0.053; figure 2).
Of the 52 patients who were prescribed a PPI for the first time, 47 were given omeprazole (figure 3) with mean INR values of 2.47 (just before) and 2.46 (just after) the treatment with omeprazole (P = 0.814). The range of variation in the INR result was less than 1 point in 91.5% of the patients (n=43) treated with omeprazole. Furthermore, there were no statistically significant differences in the percentage of patients with an INR value within the range of good control when compared with the values taken before and after the treatment with omeprazole (table 2). Of the 47 patients who were prescribed omeprazole, 33 (70.2%) had an INR value within the therapeutic range just before the application of omeprazole. After the introduction of omeprazole, 30 of these 33 patients (90.9%) remained within the therapeutic range. Only 9% of these patients went from a situation of being under good control to one of poor control (6% by default, 3% by excess). 
During the monitoring period, three patients treated with acenocoumarol were also prescribed pantoprazole with mean INR values of 2.38 and 2.63 before and after its application (P = 0.735). Finally, two of the anticoagulated patients were started on lansoprazole during the study period and had mean INR values of 2.30 and 1.70 before and after its application (P = 0.180). Despite the fact that an insufficient number of patients was available to assess changes in good anticoagulation control following pantoprazole and lansoprazole administration, we did not observe significant differences in INR values in these two subgroups when we compared the values recorded before and after the application of these drugs. 
No significant adverse effects (bleeding, cutaneous, hematologic, gastrointestinal or hepatotoxicity) were recorded.

DISCUSSION
Summary. The results of this prospective study indicate that prescribing omeprazole for a patient currently being treated with acenocoumarol does not significantly modify the INR value or, therefore, good anticoagulation control. Therefore, this first prospective study with a relevant number of patients brings light regarding the hypothetical pharmacological interaction based solely on a single report by Garcia B et al19 regarding a case of severe haemorrhagic complications in a patient who was taking omeprazole and acenocoumarol that presented an INR mesurament of 5,7 at the fifth day after the introduction omeprazole.
The lists of interactions with warfarin have been extrapolated to acenocoumarol, as both are structurally-related coumarin molecules that are mirror images or chiral, with two different enantiomers: R in acenocoumarol, which provides its anticoagulant activity and rapid clearance, and the S-enantiomer, which is the active part of warfarin. These drugs present marked pharmacokinetic differences, a half-life of 8�11 hours for acenocoumarol versus 30 hours for warfarin, due to the different stereoselective metabolism in the enzymes involved in the cytochrome P45013,15,25. 

Strengths and limitations. This work is of interest due the methodology: prospective monitoring, longitudinal long-follow-up (18 months) that included all patients treated in primary health care centers with all the INR values. And also because of the limited literature on this subject and the impact that it may have on the management of the patient's healthcare.
The previous works in this line share the conclusions that there are no significant changes in mean INR with the omeprazole administration (2.47 pre-omeprazole and 2.46 post-omeprazole; P = 0.814). Furthermore, we did not find any differences in the percentage of patients and tests with an INR value within the range of good control. We can conclude that omeprazole does not have a significant influence on the anticoagulant effect of acenocoumarol.
Among the limitations of this study we would highlight the sample size, which does not allow us to compare the different subgroups of PPIs. Secondly, it does not take into account external confounding factors that affect INR, such as the consumption of alcohol, changes in diet, or intercurrent diseases that alter the metabolism (infectious, hepatic�). We also consider that the publication of this study may arrive too late as the appearance on the market of new direct thrombin inhibitor oral anticoagulants (dabigatran, apixaban �) which do not require controls may eventually replace coumarin anticoagulants, even if only for commercial reasons.

Comparison with existing literature. In 1995, Duursema et al16 published a randomized, placebo-controlled, double-blind study in 26 healthy males who were administered 40 mg of pantoprazole, or placebo and a single oral dose of 25 mg of warfarin, for 8 days. They concluded that pantoprazole did not alter the pharmacokinetics of warfarin. This study and a revision made by Steinijans et al23 in 1996 regarding pantoprazole interactions have set the current standard for prescribing. The statement that pantoprazole is the only PPI that does not interfere with oral coumarin anticoagulants does not seem true despite the use of pantoprazole in patients treated with acenocoumarol is advised by various reference publications on interactions9,10,20.
Labenz et al24 reviewed the Food and Drug Administration database in 2003 searching adverse effects and drug interactions with omeprazole, lansoprazole, and pantoprazole after their commercialization in the United States. They concluded that interactions with oral coumarin anticoagulants are infrequent (0.09 per million packs of omeprazole, and 0.11 per million packs of lansoprazole and pantoprazole) and that each carried a similar risk, which suggests a class effect. In our case, everyday clinical experience led us to assume that there were patients taking both drugs in complete safety, as reflected in the 97 patients (37% of all those treated with acenocoumarol) who were already taking omeprazole at the start of the study. 
De Hoon et al18 designed a randomized, placebo-controlled, double-blind study in eight healthy males; the administration of 40 mg/o.d. of omeprazole (vs. placebo) for three days and a single dose of 10 mg of acenocoumarol did not show pharmacokinetics modifications nor anticoagulant activity, suggesting an in vivo different interaction profile compared to warfarin. In the same year, Vreeburg et al17 published a retrospective case-control study in which 118 patients receiving coumarin anticoagulant who were also taking omeprazole, and 299 age and sex-matched anticoagulated controls were selected. They concluded that it seemed likely that both drugs can be co-administered safely, as in 62.7% of the cases it was not necessary to change the dose of acenocoumarol compared with 56.5% of the control group. Teichert published an observational retrospective cohort study that showed a higher risk for overanticoagulation for esomeprazole and lansoprazole and a lower and non-significant risk increase for the other PPIs in patients treated with acenocoumarol.26 Becker studied the interaction between PPI and oral anticoagulants in hospitalised patients, concluding that only esomeprazole might increase the effect of phenprocoumon; nevertheless this interaction was not found between acenocoumarol and esomeprazole, omeprazole or pantoprazole.27
If omeprazole and acenocoumarol compete for the same cytochrome p450 enzymes it would be logical to think that in coumarin anticoagulated patients taking omeprazole would decrease the clearance of acenocoumarol leading to a consequent increase in INR and this would require a reduction of the dose. Vreeburg et al17 found that the dose had to be reduced in only 12.0% of the patients versus 15.4% of the controls. 
Acenocoumarol, warfarin and phenprocoumon (this is widely used in Germany, the Netherlands, Italy and Brazil) are used commonly in the Netherlands: Van Leeuwena et al28 have developed a transition algorithm that enables the dose adjustment to be estimated when changing a patient from one coumarin to another. We have only found the interaction described by Enderle et al29 between phenprocoumon and omeprazole in two of the cases. Although it may seem surprising due to the prolonged half-life of phenprocoumon (216 hours), Leiria et al30 found less hemorrhagic events and a greater percentage of patients within therapeutic levels with phenprocoumon than with warfarin. 

Implications for Research and/or practice.
The results of this study should be corroborated by a clinical trial with a suitable sample size which would control the external variables. 

Acknowledgements. 
Marta Bertran (+) for introducing the data gathered and all the administrative tasks she carried out. Dra. Estrella Barcel� and Dr. Antoni Vallano for revising and correcting the text and their many valuable contributions and suggestions. Miss Emma Mikiel for the translation, issue advice and medical writing support. Miss Paula Dotres for the issue advice and support.


How this fits in 
�	Oral anticoagulants and PPIs are frequently prescribed drugs and, therefore, the possibility of concomitant use is high.
�	Although some weak evidence showed no interactions between acenocoumarol and omeprazole, this interaction is still described to be possible in the bibliography.
�	The addition of omeprazole in patients treated with acenocoumarol did not change the INR results nor the possibility of being within the therapeutic range.
�	No significant adverse effects were observed in patients with co-administration of acenocumarol and omeprazole.


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Table 1. Indications of anticoagulation (n=260)*
Indications 					n patients (%)
Atrial fibrillation				224 (88.2%)
Mitral valvulopathy/Left atrium > 55ms		14 (5.5%)
Dilated cardiomyopathy			10 (3.9%)
TEP or DVT					8 (3.1%)
Cardiac bio prostheses 			4 (1.6%)
Mechanical prostheses 			2 (0.8%)
Factor VII/protein S deficiency	 		1 (0.4%)
Peripheral vascular disease 			1 (0.4%)
Stroke						 1 (0.4%)
* 11 (4.3%) patients had two indications; in 6 (2.3%) patients the indication was unknown
Table 2. Mean INR values and mean weekly acenocoumarol dose according the PPI concomitant treatment
Patients 							Mean INR 		Mean acenocumarol dose (mg / week)

With acenocoumarol and a PPI from the beginning of the study (n = 126)

Omeprazole (n = 97)					2.43				12.55

Other PPIs (n = 29)					2.41				12.42



With acenocoumarol and omeprazole added during the study (n = 47)

Immediately before the introduction of omeprazole 			2.47				12.72

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